Unless otherwise indicated herein, the materials described in this section are not prior art to the claims in this application and are not admitted to be prior art by inclusion in this section.
The tumor microenvironment is the cellular environment in which the tumor exists, including surrounding blood vessels, immune cells, fibroblasts, other cells, signaling molecules, and the extracellular matrix. The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells, such as in immune-editing. The tumor microenvironment has also been shown to contribute to tumor heterogeneity. Because of the importance of the tumor microenvironment in supporting cancer growth and development, the tumor microenvironment has become a target for cancer drug development.
Much effort has been devoted into developing nanoparticles as vehicles for tumor detection, imaging and diagnosis as well as for the treatment of cancer. The nanoparticle-based therapies and imaging applications can be targeted to selectively extravasate through tumor vasculature via the enhanced permeation and retention (EPR) effect. Nanoparticles have been conjugated to drugs, imaging agents, or other substances that can be delivered to specific sites either by active targeting or by size-dependent passive targeting. However, one challenge associated with use of nanoparticles in vivo is the specific delivery of nanoparticles to tumor cells. Many tumor biomarkers are also expressed on normal tissue which may result in toxicity or negatively impact the pharmacokinetics of tumor antigen-specific nanoparticles resulting from the unintended targeting of nanoparticles to normal tissue. Furthermore, nanoparticles can be deactivated or destroyed by the body before they reach their target. Accordingly, there is a need for improved nanoparticle conjugates that are shielded from degradation and/or deactivation by the body and that exploits the tumor microenvironment for targeted delivery of imaging and/or therapeutic agents to tumor cells for use in imaging, diagnostic and/or therapeutic methods to determine the medical condition of a patient and for treating cancer.